Treatment for non-insulin dependent diabetes mellitus (NIDDM; Type II diabetes) usually consists of a regimen of diet and exercise, oral hypoglycemic agents and, in more severe cases, insulin. Oral agents in common use are the sulfonylureas and the biguanides. However, while the sulfonylureas are valuable for treatment of NIDDM they may give rise to hypoglycemic episodes and exhibit other toxic manifestations which limit their use. They are also prone to a high incidence of primary or secondary failure of efficacy. Similarly, the use of biguanides has declined because of their association with incidents of toxic lactic acidosis. A continuing need for new hypoglycemic agents which may be less toxic and more efficacious is clearly evident. Pursuit of new oral agents is ongoing and a variety of new and novel compounds with hypoglycemic activity have been reported (Mohrbachet, R. J.; Kiorpes, T. C.; Bowden, C. R. Annual Reports in Medicinal Chemistry--Vol. 22, 1987, pp. 213-222, and references therein).
Ciglitazone [(.+-.)-5-[4-(1-methylcyclohexyl)methoxy]benzyl]-2,4-thiazolidinedione] (U.S. Pat. No. 4,401,902) represents a class of compounds useful for the treatment of hyperglycemia and hyperinsulinemia which only normalize these parameters, thereby avoiding hypoglycemic episodes. Other 2,4-thiazolidinedione containing compounds having antihyperglycemic activity and useful for treating diabetes have been disclosed. See: (a) Yoshioka, T.; Fujita, T.; Kanai, T.; Aizawa, Y.; Kurumada, T.; Hasegawa, K.; Horikoshi, H. J. Med. Chem. 1989, 32, 421, (b) Kanji, M.; Fujita, T. U.S. Pat. No. 4,687,777, 1987, and (c) Eggler, J. F.; Holland, G. F.; Johnson, M. R.; Volkmann, R. A. U.S. Pat. No. 4,738,972, 1988.
The compounds of the present invention also possess antihyperglycemic activity and are of novel structure. They differ from the above compounds by the attachment of a thio or sulfonyl or methylthio linking moiety at the 5-position of the 2,4-thiazolidinedione ring and by the incorporation of a lipophilic naphthalenyl group into the structure. Accordingly, the present compounds represent an important new approach for the treatment of diabetes mellitus.
Compounds in which sulfur is attached to the 5-position of a 2,4-thiazolidinedione ring have been disclosed (Japan Kokai 78 40, 770; Japan Kokai 78 46, 973; Mikrobiol. Zh. (Kiev) 1970, 32, 518-520 (Ukrain); Ger. Offen. DE 3,045,059) but differ from the compounds of the present invention in that the nitrogen of the 2,4-thiazolidinedione ring is substituted or the sulfur is in the form of a sulfonic acid. In addition, these compounds are not sulfones and do not contain a naphthalene ring. Furthermore, these compounds are claimed as having only antifouling or antibiotic properties.
The most preferred compounds of formula I are 5-[(2-naphthalenyl)sulfonyl]-2,4-thiazolidinedione and 5-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]sulfonyl]-2,4-thiazolidin edione, and the pharmaceutically acceptable cationic salts thereof.